THE 6-MINUTE WALK TEST AND OTHER CLINICAL ENDPOINTS IN DUCHENNE MUSCULAR DYSTROPHY: RELIABILITY, CONCURRENT VALIDITY, AND MINIMAL CLINICALLY IMPORTANT DIFFERENCES FROM A MULTICENTER STUDY

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Abstract

Introduction: An international clinical trial enrolled 174 ambulatory males ≥5 years old with nonsense mutation Duchenne muscular dystrophy (nmDMD). Pretreatment data provide insight into reliability, concurrent validity, and minimal clinically important differences (MCIDs) of the 6-minute walk test (6MWT) and other endpoints. Methods: Screening and baseline evaluations included the 6-minute walk distance (6MWD), timed function tests (TFTs), quantitative strength by myometry, the PedsQL, heart rate–determined energy expenditure index, and other exploratory endpoints. Results: The 6MWT proved feasible and reliable in a multicenter context. Concurrent validity with other endpoints was excellent. The MCID for 6MWD was 28.5 and 31.7 meters based on 2 statistical distribution methods. Conclusions: The ratio of MCID to baseline mean is lower for 6MWD than for other endpoints. The 6MWD is an optimal primary endpoint for Duchenne muscular dystrophy (DMD) clinical trials that are focused therapeutically on preservation of ambulation and slowing of disease progression. Muscle Nerve 48: 357–368, 2013

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Measurement of health status. Ascertaining the minimal clinically important difference.

R Jaeschke, J Singer, G H Guyatt (1989)

In recent years quality of life instruments have been featured as primary outcomes in many randomized trials. One of the challenges facing the investigator using such measures is determining the significance of any differences observed, and communicating that significance to clinicians who will be applying the trial results. We have developed an approach to elucidating the significance of changes in score in quality of life instruments by comparing them to global ratings of change. Using this approach we have established a plausible range within which the minimal clinically important difference (MCID) falls. In three studies in which instruments measuring dyspnea, fatigue, and emotional function in patients with chronic heart and lung disease were applied the MCID was represented by mean change in score of approximately 0.5 per item, when responses were presented on a seven point Likert scale. Furthermore, we have established ranges for changes in questionnaire scores that correspond to moderate and large changes in the domains of interest. This information will be useful in interpreting questionnaire scores, both in individuals and in groups of patients participating in controlled trials, and in the planning of new trials.

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The PedsQL 4.0 as a pediatric population health measure: feasibility, reliability, and validity.

James Varni, Tasha Burwinkle, Michael Seid … (2003)

The application of health-related quality of life (HRQOL) as a pediatric population health measure may facilitate risk assessment and resource allocation, the tracking of community health, the identification of health disparities, and the determination of health outcomes from interventions and policy decisions. To determine the feasibility, reliability, and validity of the 23-item PedsQL 4.0 (Pediatric Quality of Life Inventory) Generic Core Scales as a measure of pediatric population health for children and adolescents. Mail survey in February and March 2001 to 20 031 families with children ages 2-16 years throughout the State of California encompassing all new enrollees in the State's Children's Health Insurance Program (SCHIP) for those months and targeted language groups. The PedsQL 4.0 Generic Core Scales (Physical, Emotional, Social, School Functioning) were completed by 10 241 families through a statewide mail survey to evaluate the HRQOL of new enrollees in SCHIP. The PedsQL 4.0 evidenced minimal missing responses, achieved excellent reliability for the Total Scale Score (alpha =.89 child;.92 parent report), and distinguished between healthy children and children with chronic health conditions. The PedsQL 4.0 was also related to indicators of health care access, days missed from school, days sick in bed or too ill to play, and days needing care. The results demonstrate the feasibility, reliability, and validity of the PedsQL 4.0 as a pediatric population health outcome. Measuring pediatric HRQOL may be a way to evaluate the health outcomes of SCHIP.

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Evidence-based path to newborn screening for Duchenne muscular dystrophy.

Jerry R Mendell, Chris Shilling, Nancy D Leslie … (2012)

Creatine kinase (CK) levels are increased on dried blood spots in newborns related to the birthing process. As a marker for newborn screening, CK in Duchenne muscular dystrophy (DMD) results in false-positive testing. In this report, we introduce a 2-tier system using the dried blood spot to first assess CK with follow-up DMD gene testing. A fluorometric assay based upon the enzymatic transphosphorylation of adenosine diphosphate to adenosine triphosphate was used to measure CK activity. Preliminary studies established a population-based range of CK in newborns using 30,547 deidentified anonymous dried blood spot samples. Mutation analysis used genomic DNA extracted from the dried blood spot followed by whole genome amplification with assessment of single-/multiexon deletions/duplications in the DMD gene using multiplex ligation-dependent probe amplification. DMD gene mutations (all exonic deletions) were found in 6 of 37,649 newborn male subjects, all of whom had CK levels>2,000U/l. In 3 newborns with CK>2,000U/l in whom DMD gene abnormalities were not found, we identified limb-girdle muscular dystrophy gene mutations affecting DYSF, SGCB, and FKRP. A 2-tier system of analysis for newborn screening for DMD has been established. This path for newborn screening fits our health care system, minimizes false-positive testing, and uses predetermined levels of CK on dried blood spots to predict DMD gene mutations. Copyright © 2012 American Neurological Association.

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Author and article information

Journal

Journal ID (nlm-ta): Muscle Nerve

Journal ID (iso-abbrev): Muscle Nerve

Journal ID (publisher-id): mus

Title: Muscle & Nerve

Publisher: Blackwell Publishing Ltd

ISSN (Print): 0148-639X

ISSN (Electronic): 1097-4598

Publication date (Print): September 2013

Publication date (Electronic): 17 July 2013

Volume: 48

Issue: 3

Pages: 357-368

Affiliations

[1 ]Department of Physical Medicine and Rehabilitation, Neuromuscular Medicine and Rehabilitation Research Center, University of California Davis School of Medicine Davis, California, 95817, USA

[2 ]Department of Neurology, Washington University School of Medicine St. Louis, Missouri, USA

[3 ]Institute of Genetic Medicine, Newcastle University Newcastle upon Tyne, UK

[4 ]Department of Physical Therapy, University of Utah School of Medicine Salt Lake City, Utah, USA

[5 ]Department of Physical Therapy, Children's Hospital of Philadelphia Philadelphia, Pennsylvania, USA

[6 ]PTC Therapeutics, South Plainfield New Jersey, USA

Author notes

Correspondence to: C.M. McDonald; e-mail: cmmcdonald@ 123456ucdavis.edu

The study was sponsored by PTC Therapeutics, Inc. (South Plainfield, New Jersey, USA), which was responsible for all aspects of the study, and by a grant from the FDA Office of Orphan Products.

Disclosures: C.M.M is a member of the Cooperative Neuromuscular Research Group (CINRG) Executive Committee and has served on advisory committees for PTC Therapeutics, Inc., Sarepta Therapeutics, Inc., GlaxoSmithKline, Prosensa, Halo Therapeutics, Shire HGT, Cardero Therapeutics, and Novartis AG. E.K.H. is a member of the CINRG Executive Committee and has served as a consultant for Genzyme Corporation and PTC Therapeutics, Inc. R.T.A. has served as a consultant for PTC Therapeutics, Inc., and Sarepta Therapeutics. J.M.F. serves on a scientific advisory board for Prosensa, on the editorial board of Neuromuscular Disorders, and serves/has served as a member of the CINRG Executive Committee and as a consultant for Prosensa, GlaxoSmithKline, Genzyme Corporation, PTC Therapeutics, Inc., and Acceleron Pharma. M.E. has served as a clinical evaluator trainer for PTC Therapeutics, and as a consultant for Prosensa and GlaxoSmithKline. E.G. has served as a clinical evaluator trainer for PTC Therapeutics. A.M.G. has served as a clinical evaluator trainer for PTC Therapeutics. R.S. is the Chief Medical Officer for PTC Therapeutics. J.B. is the Vice President for Clinical Development at PTC Therapeutics. G.E. is the Executive Director of Biostatistics at PTC Therapeutics. A.R. is the Director of Clinical Development at PTC Therapeutics. S.W.P. is the Chief Executive Officer and founding scientist, PTC Therapeutics, Inc.

[*]

Collaborating authors are listed in Appendix 1. Other members of the PTC124-GD-007-DMD Study Group are listed in Appendix 2 in the Supporting Information.

Article

DOI: 10.1002/mus.23905

PMC ID: 3826053

PubMed ID: 23674289

SO-VID: 9693c816-211b-4ebe-a2c6-3a28363c02aa

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Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

THE 6-MINUTE WALK TEST AND OTHER CLINICAL ENDPOINTS IN DUCHENNE MUSCULAR DYSTROPHY: RELIABILITY, CONCURRENT VALIDITY, AND MINIMAL CLINICALLY IMPORTANT DIFFERENCES FROM A MULTICENTER STUDY

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Most cited references 60

Measurement of health status. Ascertaining the minimal clinically important difference.

The PedsQL 4.0 as a pediatric population health measure: feasibility, reliability, and validity.

Evidence-based path to newborn screening for Duchenne muscular dystrophy.

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